Microneedles and microneedle fabrication

ABSTRACT

A master mould is made by wire cutting a plate in two or more directions to provide a base with an array of master mould needles protruding therefrom. The size and shape of the master mould needles can readily be varied by varying the angles of upward and downward cuts in the two or more directions. The master mould is used to make a secondary mould by hot embossing a secondary mould plate onto the master mould. This forms through-holes in the secondary mould. The secondary mould is plated with a layer of metal, which forms a microneedle array.

FIELD OF THE INVENTION

The present invention relates to microneedles. In particular it relatesto the fabrication of microneedles, for instance in arrays, and tofabricated microneedles.

BACKGROUND TO THE INVENTION

Microneedles are small needles, typically in the range of from 1 μm(micron) to 3 mm long and from 10 nm to 1 mm in diameter at their bases,although the ranges can be wider, for instance up to 10 mm long and 2 mmat their bases. Microneedles typically have applications in biomedicaldevices, for instance for transdermal drug delivery. Existingmicroneedle fabrication techniques tend to produce microneedles that aretoo soft (made of polymeric materials), too brittle (made of silicon) ortoo costly, or tend to be too unreliable. For transdermal drug deliveryapplications, where penetration of the outer skin (stratum corneum) isnecessary, there are minimum requirements for the strength and ductilityof a microneedle. Prices should be low, as microneedles are usuallysingle-use products.

European Patent Application Publication No. EP-A1-1,088,642, publishedon 4 Apr. 2001 in the name of Becton Dickinson & Co. describes a methodof fabricating an array of solid microneedles by moulding. A siliconmaster mould member with a recessed surface is placed into a mouldcavity. A plastic material is pumped into the mould cavity. Microneedlesare formed in the recesses in the master mould member.

European Patent Application Publication No. EP-A1-1,287,847, publishedon 5 Mar. 2003 in the name of Lifescan, Inc. describes a method offabricating hollow microneedles by plastic injection moulding. The mouldis made of two parts. The top part has a conical recess within itsmoulding surface. One of the top and bottom parts has a protrusionextending to the moulding surface of the other part for forming theneedle lumen.

U.S. Pat. No. B1-6,334,856, issued on 1 Jan. 2002 to Allen et al.describes various ways of making arrays of hollow microneedles. In oneexample masks are formed on the tips of solid microneedles of a siliconmicroneedle array, a layer of silicon dioxide or metal is coated ontothe microneedle array, and the silicon is etched away to leave a hollowmicroneedle array of metal or silicon dioxide. In another example alayer of epoxy is cast onto an array of solid silicon microneedles. Thelevel of the epoxy is reduced to below the tips of the microneedles. Thesilicon array is removed, leaving an epoxy secondary mould. A Ti—Cu—Tiseed layer is splutter-deposited onto the epoxy secondary mould andNi—Fe electroplated onto the seed layer. The epoxy layer is thenremoved, leaving an array of hollow metal microneedles.

U.S. Pat. No. B1-6,379,324, issued on 30 Apr. 2002 to Gartstein et al.describes various ways of making arrays of hollow microneedles. One wayinvolves self-moulding a polymer film over micro-pillars throughheating. A second approach is to place a polymer film overmicro-pillars, heat the film and press it down over the micro-pillarsusing a recessed plate. A third way is to heat a plastic film in thelower part of a mould and to bring the upper part of the mould down ontothe lower part. The upper part of the mould has micro-recesses, withmicro-pillars protruding from their centres. As the upper part of themould comes down, the lower parts of the micro-pillars displace theplastic of the plastic film up into the micro-recesses.

SUMMARY OF THE INVENTION

According to one aspect of the invention, there is provided a method ofmanufacturing a master mould for use in making microneedles, from ablock of a first material. The method comprises cutting across the blockin at least two different directions to provide a master mouldcomprising a base surface with a plurality of master mould needlesprotruding therefrom. The master mould needles correspond to themicroneedles to be made.

According to a second aspect of the invention, there is provided amaster mould manufactured according to the first aspect.

According to a third aspect of the invention, there is provided a methodof manufacturing a secondary mould for use in making microneedles. Themethod comprises: providing a master mould, forming a secondary mouldand removing the secondary mould from the master mould. The master mouldis as manufactured according to the second aspect. The secondary mouldis formed on the master mould, with through-holes therethrough, thethrough-holes corresponding to the master mould needles. Thethrough-holes extend from a first surface of the secondary mould, incontact with the master mould base surface during forming of thesecondary mould, to an opposing, second surface of the secondary mould.

According to a fourth aspect of the invention, there is provided a mouldfor a secondary mould. The mould for a secondary mould comprises amaster mould as manufactured according to the second aspect. The mastermould base surface forms a first surface of the cavity of the mould fora secondary mould. The master mould needles extend into the cavitytowards a second, opposing surface of the cavity.

According to a fifth aspect of the invention, there is provided a methodof manufacturing a secondary mould for use in making microneedles. Themethod comprises manufacturing a secondary mould according to the thirdaspect by injection moulding the secondary mould into the mould for asecondary mould of the fourth aspect.

According to a sixth aspect of the invention, there is provided asecondary mould manufactured according to the third or fifth aspects.

According to a seventh aspect of the invention, there is provided asecondary mould for use in making microneedles. The secondary mouldcomprises: a plurality of through holes and a plurality of grooves. Theplurality of through holes extend through the secondary mould from afirst surface to a second, opposing surface. The plurality of groovesextend in the second surface of the secondary mould. The groovesintercept the through holes near the second surface.

According to a eighth aspect of the invention, there is provided amethod of manufacturing microneedles. The method comprises: providing asecondary mould, forming a microneedle layer and removing themicroneedle layer from the secondary mould. The secondary mould isprovided according to the third or fifth aspect or the secondary mouldis as defined in the sixth or seventh aspect. The microneedle layer isformed onto a first surface of the secondary mould and within thethrough-holes of the secondary mould.

According to an ninth aspect of the invention, there is provided amicroneedle mould, comprising a secondary mould according to the sixthor seventh aspect, with the first surface of the secondary mould forminga first surface of a microneedle mould cavity and the secondary mouldthrough-holes extending into the first surface of the microneedle mouldcavity.

According to an tenth aspect of the invention, there is provided amethod of manufacturing microneedles according to the eighth aspect,using the microneedle mould of the ninth aspect.

According to an eleventh aspect of the invention, there is provided oneor more microneedles manufactured according to the eighth or tenthaspect.

Thus the invention in one embodiment is able to provide master mould bywire cutting a plate in two or more directions to provide a base with anarray of master mould needles protruding therefrom. The size and shapeof the master mould needles can readily be varied by varying the anglesof upward and downward cuts in the two or more directions. The mastermould is used to make a secondary mould by hot embossing a secondarymould plate onto the master mould. This forms through holes in thesecondary mould. The secondary mould is plated with a layer of metal,which forms a microneedle array.

INTRODUCTION TO THE DRAWINGS

The invention is now further described by way of non-limitative exampleswith reference to the accompanying drawings, in which:

FIG. 1 is a view of a master mould according to an embodiment of theinvention;

FIG. 2 is a side view of a plate to be cut into the master mould of FIG.1, showing the path a wire takes during one wire cutting pass;

FIGS. 3A and 3B are views of the plate of FIG. 2 at different timesduring the cutting process;

FIG. 4 is an isometric view of a master mould with 64 (8×8) mould needlearrays;

FIG. 5 is a flowchart relating to the manufacture of a master mouldaccording to an exemplary embodiment;

FIGS. 6A and 6B are views of an embossing process for making a secondarymould according to an embodiment of the invention;

FIG. 7A is a cross section through a portion of a secondary mould;

FIG. 7B is an enlarged view of an opening in the secondary mould of FIG.7A;

FIG. 8 is a flowchart relating to the manufacture of a secondary mouldaccording to a further exemplary embodiment;

FIGS. 9A and 9B show the use of the secondary mould of FIG. 7A in themanufacture of a microneedle array;

FIG. 10A is an isometric view of e microneedle array fabricated usingthe secondary mould of FIG. 7A;

FIG. 10B is an enlarged view of a microneedle of the array of FIG. 10A;

FIG. 11 is a flowchart relating to the manufacture of microneedles;

FIG. 12 is a side view of a plate to be cut into a master mould, showingan alternative path a wire takes during one wire cutting pass;

FIGS. 13A to 13D are enlarged views of alternative shapes of four-sidedmaster mould needles;

FIGS. 14A to 14I depict various aspects of a wire cutting process tofabricate a master mould with triangular pyramid master mould needles.

FIG. 15A to 15D depicts geometric variations (cross sections) of a mouldneedle through three wire cut passes;

FIGS. 16A to 16H depict various aspects of three wire cut passes used tofabricate a master mould with hexagonal pyramid master mould needles;

FIG. 17A to 17J depict various aspects of four wire cut passes used tofabricate a master mould with octagonal pyramid master mould needles;

FIG. 18 is a flowchart relating to the manufacture of an alternativesecondary mould according to a further exemplary embodiment;

FIG. 19A is a cross section through a portion of a modified secondarymould;

FIG. 19B is an enlarged view of an opening in the modified secondarymould of FIG. 17A; and

FIG. 18C is an enlarged view of a triangular microneedle made from themodified secondary mould of FIG. 18A.

DETAILED DESCRIPTION

In the drawings, like numerals on different Figures are used to indicatelike elements throughout.

A method of fabricating microneedles as described herein typicallyinvolves three main steps:

(i) making a master mould;

(ii) making a secondary mould; and

(iii) forming the microneedles.

(i) Making a Master Mould

A master mould 10 according to a first embodiment of the invention isshown in FIG. 1. The master mould 10 has a generally parallelepiped base12 from which extend an array of master mould needles 14 from one face.For simplicity only a single master mould needle array is shown in theFigures although fabrication would normally involve an array of manysuch arrays formed on the master mould and secondary mould and on theproduct on which the microneedles are formed.

Making the master mould 10 according to this embodiment involvesprecision machining. A block of material, in this exemplary embodimentin the form of a parallelepiped tool steel plate (for example AISI A2 oranother steel alloy designation) is hardened first. Then all thesurfaces are mirror finished. After the finishing, one side of the plateis cut by precision wire cutting (or other precision machining, forexample CNT machining), as shown with reference to FIGS. 2, 3A and 3B.

FIG. 2 is a side view of a parallelepiped tool steel plate 16 withmirror finished surfaces, to be cut into the master mould of FIG. 1,showing the path a wire takes during one wire cutting pass. FIGS. 3A and3B are views of the plate of FIG. 2 at different times during thecutting process. FIG. 3A is an isometric view of the same tool steelplate 16 after one pass, in an X direction. FIG. 3B is an isometric viewof the same tool steel plate 16 after one pass, in an X direction andhalf a pass in a Y direction.

The first pass of the wire cutting is conducted in the X direction. FIG.2 shows the wire cutting line 18. The wire cutting line 18 extendshorizontally through the plate 16, at a base level for a base cuttingportion 18 a, until the position of the first master mould needle line,at which point the wire cutting line 18 extends upwards along a firstsloped cutting portion 18 b, at a upward cut angle α, being the angle tothe surface of the base 12 at which the first sides of the master mouldneedles extend. At the top surface of the plate 16, the wire cuttingline 18 extends downwards again towards the base level. The wire cuttingline 18 extends downwards along a second sloped cutting portion 18 c, ata downward cut angle β, being the angle to the surface of the base 12 atwhich the second sides of the master mould needles, opposing the firstsides, extend. In this embodiment the upward and downward cut angles α,β are equal, thus first and second sides of the master mould needles areisosceles. In the first pass, this pair of upward and downward cuts, thefirst and second sloped cutting portions 18 b, 18 c, creates a ridge 20between two base cutting portions 18 a. The wire cutting line 18continues horizontally again along the base level for another basecutting portion 18 a to the position of the next master mould needle 14,at which point the wire cutting line 18 extends upwards again and thendownwards again, thus cutting another ridge 20. This continues untilthere are as many ridges 20 as there are to be master mould needles inthe X direction.

Ideally at the top of the upward cut, the downward cut beginsimmediately. However, current wire cutting machines, no matter howaccurate they are, always have precision limitations. Thus, when thewire reaches the top of one ridge 20, in practice it must move laterallyto some extent (typically 1-20 μm [microns]), before it can go downward.Thus, in practice, the formed ridges 20 and later formed mould needles14 currently have small flat top surfaces instead of perfect sharp tips.Where the ridges 20 and mould needles 14 appear in the drawings ashaving perfect sharp tips, instead of small flat tip surfaces, this isfor simplicity.

After the first cutting pass, the top part of the plate 16 is removed,leaving parallel ridges on one surface of the steel plate, as appear inFIG. 3A. Then the plate 16 (or the wire cutting tool) is turned 90degrees around the Z-axis (the direction orthogonally down through theplate 16). A second wire cutting pass in the Y direction is nowconducted. This follows the same path as the first pass, as shown inFIG. 2, except that it is now in a direction at 90 degrees to thedirection of the first cut. The upward and downward cuts are at thirdand fourth side angles. As there is already a first cut, the second wirecutting pass produces individual master mould needles 14, instead ofcutting a second row of ridges. FIG. 3B shows the plate 16 half waythrough the second wire cutting pass. Some master mould needles 14 havebeen produced and the ridges 20 still extend half way along the plate.At the end of the second wire cutting pass, the plate appears as inFIG. 1. In this embodiment, each master mould needle has the same shapeof a square pyramid frustum.

FIGS. 1 to 3 show the fabrication process for a master mould having onlyone master mould needle array. Several tens or even more master mouldneedle arrays can be formed by two wire cutting passes, when a largersteel plate is used. For example, FIG. 4 is an isometric view of amaster mould 10 with 64 (8×8) master mould needle arrays fabricated intwo wire cutting passes. A single master mould needle 14 is shownenlarged.

The master mould need not be steel but can be made from anothermetal/alloy such as an aluminium alloy, zinc alloy, etc. One or morehard coatings, for example, diamond carbon coating, a diamond likecarbon coating (DLC), an electroless Ni coating, a hard chrome coating,a nitride coating, a carbide coating or a boride coating may be appliedonto the master mould surface and master mould needles. This to increasethe hardness of the master mould, to extend the life of the mastermould. Additionally or instead there may be added a release layercoating layer, for example an aluminium coating, a titanium coating, achromium coating, a carbon coating, a diamond like carbon coating orsome or appropriate coating to facilitate the release of a plate used inthe creation of a secondary mould. Some of the coatings can increasehardness and act as a release layer.

A flowchart describing the steps involved in making the master mouldaccording to this embodiment is shown in FIG. 5. At step S100 a block ofmaterial is prepared. The block is cut in a first direction at stepS102, to form a plurality of ridges, and in a second direction at stepS104, to turn the ridges into master mould needles.

(ii) Making a Secondary Mould

An embossing process for making a secondary mould is shown schematicallyin FIGS. 6A and 6B, using a master mould 10 for four microneedle arraysas an example.

As appears in FIG. 6A, the master mould 10 is placed horizontally on thebottom surface of a hot press (not shown) with the master mould needles14 facing upwards. An embossing plate 22 is placed on top of the mastermould 10. The embossing plate 22 of this embodiment is made from athermoplastic polymeric material (such as polycarbonate, nylonpolyimide, PMMA, etc.) and is of a thickness equal to the height of thefinal microneedles that are to be fabricated. The plate thickness ispreferably between 50 to 2000 μm (microns) but the range can be larger.A top plate 24 is placed above the embossing plate 22. The top plate 24has arrays of through-holes 26 that are in alignment with the mastermould needle arrays of the master mould 10. The through-holes 26 arecylindrical in shape, each with a cross sectional area large enough tocontain the square cross section of the master mould needle 14penetrating in.

The combined thickness of the embossing plate 22 and the top plate 24 islarger than the height of the master mould needles 14. The height of themaster mould needles 14 is greater than that of the final microneedlesto facilitate their full penetration through the embossing plate 22.

The holes 26 in the top plate 24 do not need to be through-holes. Theycould simply be recesses in the underside of the top plate 24 toaccommodate the tips of the master mould needles 14 extending above thetop surface of the embossing plate 22. Likewise the holes 26 in the topplate 24 do not need to be cylindrical; they could be square,frusto-conical, frusto-pyramidal or any other shape to accommodate thetips of the master mould needles 14 extending above the top surface ofthe embossing plate 22.

The top plate 24 is made from a material that can sustain a subsequentheating temperature, for instance steel, which may be of the same typeas that from which the master mould 10 is made. Alternatively, the topplate 24 is made from other materials, for example aluminium or analuminium alloy (or some other metal or alloy) or another thermoplasticmaterial with a working temperature higher than that of the material ofthe embossing plate 22.

The master mould 10 is heated to a first temperature, a little over thesoftening temperature of the embossing plate 22 (for polycarbonate, itis above 150° C., in the range between 150 and 200° C.). At the firsttemperature, the top plate 26 is pressed down by the upper plate of thehot press, at the same temperature, forming a sandwich block 28 (of thethree layers: the master mould 10, the embossing plate 22 and the topplate 24), as shown in FIG. 6B.

The temperature is allowed to drop to a second value, lower than thesoftening temperature of the embossing plate 22. At this secondtemperature value, the embossing plate 22 hardens. Then the top plate 24is removed and the embossed embossing plate is released from the bottommaster mould 10, with square pyramid frustum through-holes ‘printed’into it. The embossed embossing plate forms a secondary mould. Themaster mould 10 and the top plate 24 are reusable for making furthersecondary moulds.

FIG. 7A is a cross section through a portion of a secondary mould 30,showing the square pyramid frustum through-holes 32. FIG. 7B is anenlarged isometric view of one such through-hole 32. These Figures areinverted relative to the orientation of FIGS. 6A and 6B.

In another exemplary embodiment, the orientation of the embossingprocess can be inverted. The master mould can be placed on the top, withthe master mould needles facing down, the embossing plate below themaster mould and the top (now the bottom) plate at the bottom.

In a further alternative process, another plate is used instead of thetop plate, without any openings on it. It is made of the same materialas the embossing plate 22 or of a material of the same or a lowersoftening temperature. A separation film may then be provided betweenthe embossing plate 22 and the new top plate to prevent the two platesbonding together during the hot press (embossing) process. Theseparation film may be in the form of a Ti, Cr, or Al layer, applied byPVD, CVD, evaporation, etc., or simply a layer of liquid injection mouldrelease agent film.

A flowchart describing the steps involved in making the secondary mouldaccording to this embodiment is shown in FIG. 8. At step S110 a mastermould is provided. At step S112 a secondary mould plate is placed on topof the master mould. The secondary mould plate is heated and presseddown at step S114 to form through-holes through the secondary mouldplate. The secondary mould is removed from the master mould at stepS116.

(iii) Forming the Microneedles

The embossing plate 22 embossed during the hot embossing process, withsquare pyramid frustum through-holes 32 is a secondary mould 30.Microneedle arrays are made using a secondary mould 30, as describedwith reference to FIGS. 9A and 9B.

The secondary mould 30 is metallised by depositing a thin conductiveseed film 34 (such as Ni, Ti, Cr, Al, Ag or another conductive film)onto a top surface 36 of the secondary mould 30, as shown in FIG. 9A.The top surface 36 of the secondary mould 30 for this purpose is thesurface with the larger openings to the pyramid frustum through-holes 32(it is the bottom surface during the formation of the secondary mould 30as described earlier with reference to FIGS. 6A and 6B). The method usedfor depositing the seed film 34 can be PVD, CVD, thermo-evaporation,electroless plating of Ni or another metal, through the silver-mirrorreaction (for a thin Ag coat) or some other process. This depositioncovers the whole of the top surface 36 as well as lining thethrough-holes 32. The deposited layer 34 typically has a substantiallyconstant thickness, and is typically within the range of between 10 nmand a few microns (or more).

Electroforming of Ni or Ni/Fe alloy or another metal/alloy is thenconducted to provide the microneedle layer 38. The microneedle layer 38is on top of the thin metal seed film 34 on the secondary mould 30 andin the through-holes 32, as shown in FIG. 9B. The thickness of theplated metal/alloy preferably ranges from 20-100 μm (microns) (althoughwider ranges are also possible). Other techniques can be used instead ofelectroforming, for instance electroless plating or vapour deposition,particularly for depositing non-metal layers, such as carbon, althoughthese may be expensive.

The plated metal/alloy structure, microneedle layer 38, with or withoutthe thin metal seed film 34, is released from the secondary mould 30.The released structure is the desired microneedle array product 40, asshown in FIG. 10A, with an array of the desired microneedles 42. Forsimplicity only a single microneedle array is shown in FIG. 10A,although fabrication would normally involve an array of many such arraysbeing formed (for instance 64 (8×8) arrays, using the master mould ofFIG. 4). FIG. 10B is an enlarged view of one of the frusto-pyramidalmicroneedles 42. The microneedles are shown here as being hollow.However, they can be solid if desired, if the metal or other material isdeposited to a sufficient thickness.

The released secondary mould 30 can be reused or disposed after therelease.

A flowchart describing the steps involved in making the microneedlesaccording to this embodiment is shown in FIG. 11. At step S120 asecondary mould is provided. At step S122 a thin electrically conductiveseed film is formed on top of the secondary mould and on thethrough-hole walls. A metal layer is electroformed onto the seed layeron top of the secondary mould and in the through-holes, in step S124.The microneedles are released from the secondary mould at step S126.

Alternative Geometries

The sizes and geometries of the final microneedles 42 on the microneedlearray product 40 can be adjusted by changing the wire-cutting route 18in making the master mould. With the cutting line 18 shown in FIG. 2(repeated in the Y direction), the four side surfaces of the mastermould needles 14 (and therefore the final microneedles 42) have the sameshape, the same inclination angles with respect to the bottom surface,and a square cross section. By changing the uphill and downhill cutangles α, β of the cutting route, the master mould needle shape can beadjusted. Such master moulds of different geometries can be used to formsecondary moulds of different geometries in the same manner as isdescribed above. These secondary moulds of different geometries can beused to make microneedle array products, again in the same manner asmentioned above.

FIG. 12 is a side view of a parallelepiped tool steel plate 16 withmirror finished surfaces, similar to FIG. 2, to be cut into a mastermould, showing the path a wire takes during one wire cutting pass for afirst alternative shape of master mould needles 50.

FIG. 13A is an enlarged view of a first alternative shape of mastermould needle 50. In this case the upward cut angle α=90 degrees, whilstthe downward cut angle β<90 degrees, in the X direction, whilst theupward and downward cut angles in the Y direction are unchanged from thefirst embodiment.

FIG. 13B is an enlarged view of a second alternative shape of mastermould needle 52, where the upward cut angle α=90 degrees, and thedownward cut angle β<90 degrees, in both the X and Y directions.

FIG. 13C is an enlarged view of a third alternative shape of mastermould needle 54, where the upward cut angle α>90 degrees, and thedownward cut angle β<180 degrees—the upward cut angle α, in the Xdirection, whilst the upward and downward cut angles in the Y directionare unchanged from the first embodiment.

FIG. 13D is an enlarged view of a fourth alternative shape of mastermould needle 56, where the upward cut angle α>90 degrees, and thedownward cut angle β=180 degrees —the upward cut angle α, in the Xdirection, whilst the upward and downward cut angles in the Y directionare both at 90 degrees. This master mould needle 56 is a slantedparallelepiped needle.

Such varieties make the resistance of the microneedle penetration intothe skin adjustable according to applications.

For slanted master mould needles, as in FIGS. 13C and 13D of the slantedmicroneedle with one side angle greater than 90 degrees, the pressingdirection in making the secondary mould needs to be likewise slanted tofacilitate the penetration of the master mould through the embossingplate to form the required shape of the opening.

In the embodiment of FIG. 13D, the top of the master mould needle 56 isnot a single point. This means that where the cutting process reachesthe top of the plate in the upward cut, it is no angled down immediatelyagain but moves forwards a little along the top of the plate 16 first.This also may happen where two faces of the master mould needle meet atthe top of the plate 16 or where the upward and downward cut angles α,βare so steep that the sides of the master mould needle would meet abovethe surface level of the plate 16.

In the above-described embodiments, the master mould needles and theultimately produced microneedles have quadrilateral cross-sectionsarising from a square base. By changing the number of wire cuttingpasses and/or the angle through which the plate 16 is turned betweeneach cut, other shapes are produced.

For instance, master mould needles having quadrilateral cross-sectionsarising from a parallelogram base can be derived by using only two wirecutting passes, where the angle through which the plate is turnedbetween the first pass and second pass is not 90 degrees, for instance60 degrees.

Master mould needles having triangular cross-sections arising from atriangular base can be derived by using three wire cutting passes. Thetriangular base can be equilateral if the angle through which the plateis turned between the first pass and second pass and between the secondpass and the third pass is 120 degrees. Such a regular triangular mastermould needle 60 is shown in FIG. 14A. In this case the upward cut angleα of a pair of upward and downward cuts defines one face of each needlebut the downward cut angle β of the pair of upward and downward cutsdoes not. The downward cut angle β of each pair of cuts defines a planecontaining the line joining the other two sides of the needle notdefined by the upward cut of that pair. Once the angle of each surfaceof the master mould needle (which is the upward cut angle α in each passin this embodiment) and the height of the master mould needle aredecided, the downward position and cut angle β can be determinedprecisely by mathematical calculation (even for non-regular triangles,although for non regular triangles formed by three cuts, the formedmicroneedles are not uniformly distributed on the base surface). Thedistance the wire passes through between finishing an upward cut andstarting a downward cut is defined by the line “ab” of FIG. 14A. Thedistance between where the wire starts on its upward cut and where itfinishes its downward cut is defined by the line “a′b′”. The points “a”and “a′” are defined as the centre points of the top line and bottomline, respectively, of a first side (cut in the upward cut, the firstcutting portion). The points “b” and “b′” are defined as the top andbottom, respectively, of the line joining the other two, adjacent faces.“h” is the vertical height of the master mould needle.

Various aspects of the wire cutting process for a master mould withregular triangular cross section master mould needles 60 are shown inFIGS. 14B to 14I.

FIG. 14B is similar to FIGS. 2 and 12 and is a side view of aparallelepiped tool steel plate 16 with mirror finished surfaces, to becut into a master mould, showing the path a wire takes during one wirecutting pass for regular triangular cross section master mould needles60.

FIG. 14C is a top plan view of the steel plate 16 after a first pass P1.FIG. 14D is an isometric view of the same tool steel plate 16 of FIG.14C.

FIG. 14E is a top plan view of the steel plate 16 after a second passP2. FIG. 14F is an isometric view of the same tool steel plate 16 ofFIG. 14E.

FIG. 14G is a top plan view of the steel plate 16 after a third pass P3.FIG. 14H is an isometric view of the same tool steel plate 16 of FIG.14G. FIG. 14I is a cross-section through the regular triangular mastermould needle 60 (at any point), showing the relationship between thethree passes P1, P2, P3 and their relative angles.

The regular triangular master mould needle 60 of FIG. 14A can also beobtained by rotating the plate through 60 degrees between each pass. Inthis case, the upward cuts of the first and third passes define two ofthe faces of each master mould needle, whilst the downward cuts of thesecond pass define one of the surfaces of each master mould needle, withthe upward cuts during the second cutting pass defining the planescontaining the lines joining the other two faces. Alternatively, itcould be the downward cuts of the first and third passes which definetwo surfaces of each master mould needle, whilst the upward cuts of thefirst and third passes define the planes containing the lines joiningthe other two faces.

When cutting master mould needles having triangular cross-sectionsarising from a triangular base, only one cut of each pair of upward anddownward cuts in any pass defines any of the outer surfaces of themaster mould needles. The other cut of each pair is at the angle that isrequired to cut the plane that contains the edge joining the two sidesnot being cut in that pair of cuts, or it may be shallower. This is toavoid the downward cut cutting away any material that might, otherwisebe exposed during the cutting of either of the other passes. Otherwisethis results in the production of other polygons: quadrilaterals,pentagons or hexagons, depending on how many cuts are steeper than theangle defining the plane joining the other two sides of the pyramid.

The cross sections of mould needles for these variations are shown inFIG. 15A to 15D. FIG. 15A shows (by double arrows) three wire cut passesfor a master mould with irregular triangle cross section. In each wirecut, the projection of the direction of movement of the wire on the baseplane is parallel to the projection, on the base plane, of one height ofthe triangle (the projection of the perpendicular line from one vertexto its opposite side of the triangle, that opposite side being the sidebeing cut). FIG. 15B shows a quadrilateral cross section, with one pairof parallel sides (ladder-shaped), of a mould needle formed by threewire cuts, one of which produces the two parallel sides. FIG. 15C showsa pentagonal cross section, with two pairs of parallel sides, of a mouldneedle formed by three wire cuts, two of which produce the two pairs ofparallel sides. FIG. 15D is an irregular hexagonal cross section of amould needle. Each side of the cross section is parallel to the oppositeside. It is formed by three wire cuts, each of which produces one pairof the parallel sides.

For a mould needle with an hexagonal cross section, if the upward anddownward cuts are made at the same angles in each of three passes, eachat 120 degrees to each other (or 60 degrees as appropriate), a regularhexagonal master mould needle is produced. The process is shown in FIGS.16A to 16H.

FIG. 16A is an enlarged view of a regular hexagonal master mould needle62. FIG. 16B is a top plan view of a steel plate 16 after a first passP1. FIG. 16C is an isometric view of the same tool steel plate 16 ofFIG. 16B, where the surfaces that become faces 1 and 1′ of the finalmicroneedles are exposed. FIG. 16D is a top plan view of the steel plate16 after a second pass P2. FIG. 16E is an enlarged view of a partiallyformed (rhomboidal) master mould needle within FIG. 16D, with surfacesthat become faces 1, 1′, 2 and 2′ of the final microneedles exposed.FIG. 16F is a top plan view of the steel plate 16 after a third pass P3.FIG. 16G is an enlarged view of a fully formed master mould needle 62within FIG. 16F, with final faces 1, 1′, 2, 2′, 3 and 3′. FIG. 16H is across-section through the regular hexagonal master mould needle 62 (atany point), showing the relationship between the three passes P1, P2,P3.

Similarly, it is possible to use four cutting passes, at 45 degreeintervals, to produce master mould needles with a regular octagonalcross section. The cutting process is shown in FIGS. 17A to 17J.

FIG. 17A is an enlarged view of a regular octagonal master mould needle64. FIG. 17B is a top plan view of a steel plate 16 after a first passP1. FIG. 17C is an isometric view of the same tool steel plate 16 ofFIG. 17B, where the surfaces that become faces 1 and 1′ of the finalmicroneedles are exposed. FIG. 17D is a top plan view of the steel plate16 after a second pass P2. FIG. 17E is an enlarged view of a partiallyformed (rhomboidal) master mould needle within FIG. 17D, with surfacesthat become faces 1, 1′, 2 and 2′ of the final microneedles exposed.FIG. 17F is a top plan view of the steel plate 16 after a third pass P3.FIG. 17G is an enlarged view of a partially formed (irregular hexagonal)master mould needle within FIG. 17F, with surfaces that become faces 1,1′, 2, 2′, 3 and 3′ of the final microneedles exposed. FIG. 17H is a topplan view of the steel plate 16 after a fourth pass P4. FIG. 17I is anenlarged view of a fully formed (octagonal) master mould needle 64within FIG. 17H, with final faces 1, 1′, 2, 2′, 3, 3′, 4 and 4′. FIG.17J is a cross-section through the regular octagonal master mould needle64 (at any point), showing the relationship between the four passes P1,P2, P3, P4.

It is also possible to form mould needle arrays with regular polygonalcross-section of some even higher numbers of sides. It is a mathematical(geometry) problem to decide what side numbers can be formed by limitednumbers of wire cuts across the whole plate.

The design of the master mould and in particular that of the mastermould needles is determined from the design of the desired microneedlesthrough mathematical calculations.

As with the master mould needles with square cross sections, theinclinations of the side surfaces of the triangular master mould needlescan also be adjusted by adjusting the upward and downward cut angles α,β. When the upward cut angle α=90 degrees, one side surface of themaster mould needles becomes normal to the bottom plane. When thedownward cut angle β=90 degrees, the corresponding intersection linebetween two side surfaces becomes normal to the bottom surface. Othervariations are also possible by changing the inclination angles. Thesame applies to master mould needles of other shapes.

Alternative Methods of Fabricating the Secondary Mould

One alternative way of fabricating the secondary mould is throughelectro-discharge machining (EDM). A master mould is made as describedabove, the master mould needles forming an array of EDM electrodes. Thegeometries and dimensions of the electrode array are based on those ofthe desired microneedles. A metal/alloy plate, for instance made ofstainless steel, aluminium/aluminium alloy or nickel/nickel alloy, isplaced below the EDM electrode array. EDM is conducted to make openingsin the plate corresponding to the shapes and dimensions of the electrodearray. Subsequently, the plate with the openings is coated with aninsulating layer. The insulating layer is coated onto the bottom surfaceand all side surfaces, but not usually on the top surface (the oneformed in contact with the master mould base surface). This plate can beused as a secondary mould, in the same way as the embossed platementioned earlier is. Microneedle arrays are fabricated byelectroforming, as before. The secondary mould made in this way by EDMis a permanent one that can be reused again after release of theelectroformed microneedle arrays. One advantage this metal secondarymould has over the polymer one made through embossing is that it islonger lasting.

A flowchart describing the steps involved in making the secondary mouldaccording to this embodiment is shown in FIG. 18. At step S130 a mastermould forming an array of EDM electrodes is provided. At step S132 asecondary mould plate is placed below the master mould. EDM is conductedat step S134 to form through-holes through the secondary mould plate.The secondary mould is removed from the master mould at step S136.

In another process for making the secondary mould, it is moulded ontothe master mould, for instance by injection moulding. The master mouldprovides a first wall of the injection mould cavity, with the mastermould needles extending into the cavity towards an opposing second wall.The secondary mould is moulded into the cavity between the first, mastermould surface and the second, opposing wall. The second wall of thecavity can typically be one of two structures. In the first structure,this wall is simply a flat wall. In this case, the master mould needleheight is equal to the final needle height. The mould cavity width whenit is closed in the injection moulding operation is also equal to thefinal microneedle height. The master mould needles may extend part wayor substantially all the way to the second wall. In the secondstructure, a plurality of receiving holes (or recesses) are provided onthe second wall. The receiving holes are at positions which correspondto all the master mould needles on the first, master mould wall. Theheight of the needles is larger than the final needle height. The mouldcavity width, when it closes during the injection moulding operation, isagain equal to the final microneedle height. The depth of the holes isequal to or slightly larger than the difference between the master mouldneedle height and the cavity width. The cross section of each hole (orrecess) is just enough (in size and shape) to contain the cross sectionof the master mould needle at the height of the final needle height(i.e. at the second wall surface).

The secondary mould is fabricated by injection moulding a polymermaterial, such as (but not limited to) polycarbonate, PMMA, nylon orsilicon rubber. When silicon rubber is used, the ‘injection’ process isconducted at room temperature and the solidification is by adding incuring agent into the pre silicon rubber liquid (cold casting process).

Another alternative for making the secondary mould is by electroforminga proper metal such as (but not limited to) Ni, Ni—Fe alloy onto themaster mould (fabricated as described earlier). Proper release measuremay be needed before electroforming. This may take the form ofdepositing a thin electrically conductive layer (preferably betweenabout 100 to about 1000 nm), which does not have high adhesion to themaster mould, on the master mould surface. The non-high adhesion to themaster mould is so that the thin electrically conductive layer does notform a strong bond with the master mould. This electrically conductivelayer may, for instance be formed of aluminium, titanium or chromium.The thickness of the plated metal/alloy may be larger than the finalmicroneedle height. After release, the backside surface of theelectroformed piece (the side not in contact with the master mouldneedles during the electroforming) is ground/milled to a thickness equalto the final needle height. An electrical insulation layer is thenapplied to the back surface and all side surfaces, but not usually onthe front surface (the one formed in contact with the master mould basesurface) and not on the hole walls. The electroformed piece is usable aspermanent secondary mould for making microneedles.

A modification to the secondary mould, however it is made, is shown inFIGS. 19A and 19B. FIG. 19A is a cross section through a portion of amodified secondary mould 70; showing modified triangular pyramid frustumthrough-holes 72. FIG. 19B is an enlarged isometric view of one suchthrough-hole 72.

V-shaped grooves 74 are formed in the bottom surface of the modifiedsecondary mould 72, as it appears in FIG. 19A. The bottom surface of themodified secondary mould 70 for this purpose is the surface with thesmaller openings to the through-holes 72. The V-shaped grooves 74 runparallel to the lines of through-holes 72. Each through-hole 72 meets atleast one surface or edge of a V-shaped groove 74. Normally one of thetwo intersection lines between each V-shaped groove 74 and the bottomsurface of the modified secondary mould 72 is aligned with and meets oneof the edges of each of the smaller openings to the through-holes 72 inone line of through-holes 72. Each V-shaped groove 74 extends upwardsinto the through-holes 72, the edge of which they are aligned with andmeet. In the embodiment of FIG. 19A, the tip of the V-shaped groove 74meets an inner surface of each through-hole 72 in the line. The innersurface that the V meets is on the other side of the through-holes 72from the edge that the V-shaped groove 74 meets at the bottom surface.

The purpose of the grooves 74 is to increase the sharpness of themicroneedles fabricated from the secondary mould 70. It does this bymaking a slanted cut across the through-holes 72 that are used to formthe microneedles, with the ends of the microneedles taking the cutshapes. FIG. 19C is an enlarged view of a triangular microneedle 80,with a sharp tip 82, made from the modified secondary mould of FIG. 19A.

Such grooves can be used for other shaped microneedles, as well as thetriangular ones. The groove cross section need not be V-shaped but maytake other shapes, for instance semicircular, the chord of a circle,parabolic, etc. Individual grooves, in cross-section, have a firstgroove surface extending from the second surface of the secondary mouldto a deepest point of the groove within the secondary mould. The firstgroove surface may extend completely across the width of thethrough-holes the groove intercepts to form a single slope across thetip of the microneedles (FIG. 19C). Normally the grooves intercept overhalf the width of each through-hole (FIGS. 19D and 19E). The firstgroove surface may extend only partially across the width of thethrough-holes the groove intercepts, with a second surface of the grooveintercepting the rest of each such hole, to form two sharp tips ondifferent sides of the microneedles.

The grooves can be moulded into the plates that are formed into thesecondary moulds or machined or burned into the plates, for instance bycutting, laser ablation or milling or may be formed in the plates in anyother suitable way. Where the secondary mould is formed by moulding ontothe master mould, as mentioned above, ridges in the opposing surface ofthe mould could be provided form the grooves directly during themoulding process. Where the secondary mould is formed by EDM orelectroforming, the grooves are preferably made first, before theinsulation layer application. Then the electrical insulation layer isapplied to the secondary mould back surface and all side surfaces(including the groove surface). If the grooves are not made before theinsulation layer has been applied, a second electrical insulation layerapplication for the groove surface is needed.

Alternative Use of Secondary Mould

Earlier, microneedle arrays are described as being formed throughelectroforming on the secondary mould. As one possible alternative, thesecondary mould whether produced as described with reference to FIGS. 5Aand 5B, whether produced as described elsewhere (for instance by EDM orelectroforming) or produced in another manner, can be used as one wallof a mould, with through-holes corresponding to the mould needles of themaster mould and with or without tip needle sharpening grooves.Moulding, for instance injection moulding, onto the same face of thesecondary mould as the metal is formed onto in FIGS. 9A and 9B, followedby a release produces the microneedle array. This method can be used tocreate solid needles, for instance of a polymer material such as apolycarbonate, PMMA, nylon, etc. If the face opposing the secondarymould has protrusions corresponding in position to the through-holes inthe secondary mould, and extending to the same level as the tops of thethrough-holes in the secondary mould, but being narrower, the mouldedmicroneedles can be hollow.

The embodiments of the invention allow the easy production of strong andductile hollow microneedle arrays or solid needles, such as solidpolymer needles, on a large industrial scale. Moulds for fabricatingmicroneedles can be made using cheap polymeric materials so the mouldscan be of low cost and disposable. Moreover the exemplary method ofmaking the secondary (microneedle) mould is cheaper using the wirecutting method to make the master mould. The use of the wire cuttingmethod allows easy variation in the size and shape of the microneedles,whether regular or irregular, tapered or non-tapered, straight orslanted or of various numbers of sides. The sharpness of suchmicroneedles can be further enhanced by the use of grooves in the backof the secondary mould. This allows the easy production of sharpmicroneedles, which makes them better at penetrating the skin anddelivering the liquid into the subject. Such microneedle arrays can beused in painless injection devices to replace conventional injectionneedles/syringe.

1. A method of manufacturing a master mould for use in makingmicroneedles, from a block of a first material, the method comprising:cutting across the block in at least two different directions to providea master mould comprising a master mould base surface with a pluralityof master mould needles protruding therefrom; wherein the master mouldneedles correspond to the microneedles to be made.
 2. A method accordingto claim 1, wherein cutting across the block comprises wire cuttingacross the block.
 3. A method according to claim 1, wherein cuttingacross the block in at least two different directions comprises a cut ineach direction.
 4. A method according to claim 3, wherein individualcuts comprise: a plurality of base cutting portions, cutting the mastermould base surface; a plurality of first sloped cutting portions,cutting from the base cutting portions to the tips of the master mouldneedles; and a plurality of second sloped cutting portions, cutting fromthe tips of the master mould needles to the base cutting portions; andwherein individual base cutting portions are separated by a pair of afirst sloped cutting portion and a second sloped cutting portion; and atleast one of each pair of first and second sloped cutting portions cutsa surface of a plurality of master mould needles.
 5. A method accordingto claim 4, wherein the composition of each cut is the same.
 6. A methodaccording to claim 1, wherein the master mould needles are triangularpyramid shaped; and the master mould base surface with a plurality ofmaster mould needles protruding therefrom are provided by three cuts inthree different directions.
 7. A method according to claim 4, whereinonly one of each pair of first and second sloped cutting portions cuts asurface of a plurality of master mould needles.
 8. A method according toclaim 7, wherein the other of each pair of first and second slopedcutting portions cuts an edge of a plurality of master mould needles. 9.A method according to claim 1, wherein the master mould needles arehexagonal; and the master mould base surface with a plurality of mastermould needles protruding therefrom are provided by three cuts in threedifferent directions.
 10. A method according to claim 1, wherein themaster mould needles are square pyramid shaped; and the master mouldbase surface with a plurality of master mould needles protrudingtherefrom are provided by two cuts in two different directions.
 11. Amethod according to claim 10, wherein the two cuts are at right anglesto each other.
 12. A method according to claim 1, wherein the mastermould needles are octagonal; and the master mould base surface with aplurality of master mould needles protruding therefrom are provided byfour cuts in four different directions.
 13. A method according to claim12, wherein the four cuts are at 45 degrees to each other.
 14. A methodaccording to claim 4, when dependent on at least claim 4, wherein bothof each pair of first and second sloped cutting portions cuts a surfaceof a plurality of master mould needles.
 15. A method according to claim6, wherein the three cuts are at 60 or 120 degrees to each other.
 16. Amethod according to claim 1, further comprising coating the master mouldbase surface and the master mould needles with a hard coating.
 17. Amethod according to claim 16, wherein the hard coating comprises acoating of one or more of: a diamond carbon coating, a diamond likecarbon coating, an electroless Ni coating, a hard chrome coating, anitride coating, a carbide coating and a boride coating.
 18. A methodaccording to claim 1 further comprising: applying a thin electricallyconductive layer on the master mould surface, as a release layer.
 19. Amethod according to claim 18, where in the release layer comprises acoating of one or more of: an aluminium coating, a titanium coating, achromium coating, a carbon coating and a diamond like carbon coating.20. A master mould for use in making microneedles, which master mould ismanufactured according to the method of claim
 1. 21. A method ofmanufacturing a secondary mould for use in making microneedles,comprising: providing a master mould, which master mould is as definedin claim 20; forming, on the master mould, a secondary mould withthrough-holes therethrough, the through-holes corresponding to themaster mould needles and extending from a first surface of the secondarymould, in contact with the master mould base surface during forming thesecondary mould, to an opposing, second surface of the secondary mould;and removing the secondary mould from the master mould.
 22. A method ofmanufacturing a secondary mould for use in making microneedles,comprising: providing a master mould, which master mould is as definedin claim 20; forming, on the master mould, a secondary mould withthrough-holes therethrough, the through-holes corresponding to themaster mould needles and extending from a first surface of the secondarymould, in contact with the master mould base surface during forming thesecondary mould, to an opposing, second surface of the secondary mould;and removing the secondary mould from the master mould, whereinproviding the master mould comprises manufacturing a master mould inaccordance with the method of claim
 1. 23. A method according to claim21, wherein forming the secondary mould comprises hot embossing,electro-discharge machining, electroforming or injection moulding thesecondary mould against the master mould.
 24. A method according toclaim 21, further comprising applying an electrical insulation coatingto the surfaces of the secondary mould.
 25. A method according to claim24, wherein the electrical insulation coating is applied to the sidesand second surface of the secondary mould.
 26. A method according toclaim 21, wherein the second surface of the secondary mould comprises aplurality of grooves extending into the secondary mould, which groovesintercept the through-holes near the second surface.
 27. A methodaccording to claim 26, wherein individual grooves, in cross-section,have a first groove surface extending from the second surface of thesecondary mould to a deepest point of the groove within the secondarymould, which first groove surface extends at least part way across thewidth of the through-holes the groove intercepts.
 28. A method accordingto claim 26, wherein the grooves intercept over half the entire widthsof the through-holes.
 29. A method according to claim 26, wherein thegrooves intercept the second surface at or close to the edges of thethrough-holes at the second surface.
 30. A method according to claim 26,further comprising providing said plurality of grooves.
 31. A mould fora secondary mould, comprising a master mould as defined in claim 20,with the master mould base surface forming a first surface of the cavityand the master mould needles extending into the cavity towards a second,opposing surface of the cavity.
 32. A mould according to claim 31,wherein the second surface of the cavity comprises a plurality ofreceiving holes corresponding in position to the master mould needles,for receiving said master mould needles; the depth of the receivingholes is at least the difference between the height of the master mouldneedles and the width of the cavity between the first and secondsurfaces of the cavity; the size and shape of the holes at the secondsurface of the cavity are the same as the size and shape of the mastermould needles at the second surface of the cavity.
 33. A mould accordingto claim 31, wherein the width of the cavity between the first andsecond surfaces of the cavity is substantially the same as the height ofthe master mould needles above the master mould base surface.
 34. Amould according to claim 31, wherein the second surface of the cavitycomprises a plurality of ridges extending into the cavity.
 35. A methodaccording to claim 23, wherein forming the secondary mould comprisesinjection moulding the secondary mould within the cavity of a secondarymould injection mould.
 36. A method according to claim 35, wherein thesecondary mould injection mould is a mould for a secondary mould withthe master mould base surface forming a first surface of the cavity andthe master mould needles extending into the cavity towards a second,opposing surface of the cavity.
 37. A method according to claim 36,wherein the ridges form said grooves in the second surface of thesecondary mould
 38. A method according to claim 35, wherein forming thesecondary mould comprises injection moulding a polymer into thesecondary mould injection mould.
 39. A secondary mould manufacturedaccording to the method of claim
 21. 40. A method of manufacturingmicroneedles, comprising: providing a secondary mould, which secondarymould is as defined in claim 39; forming a microneedle layer onto afirst surface of the secondary mould and within the through-holes of thesecondary mould; and removing the microneedle layer from the secondarymould.
 41. A method according to claim 40, further comprising splittingthe microneedle layer into a plurality of microneedle portions, eachhaving one or more microneedles thereon.
 42. A method according to claim40, wherein providing the secondary mould comprises manufacturing asecondary mould forming, on the master mould, a secondary mould withthrough-holes therethrough, the through-holes corresponding to themaster mould needles and extending from a first surface of the secondarymould, in contact with the master mould base surface during forming thesecondary mould, to an opposing, second surface of the secondary mould,and removing the secondary mould from the master mould.
 43. A methodaccording to claim 40, wherein forming the microneedle layer comprisesPVD, CVD, thermo-evaporation, electroless plating or injection mouldingthe microneedle layer onto the first surface of the secondary mould. 44.A microneedle mould, comprising a secondary mould as defined in claim39, with the first surface of the secondary mould forming a firstsurface of the microneedle mould cavity and the secondary mouldthrough-holes extending into the first surface of the microneedle mouldcavity.
 45. A method according to claim 43, wherein forming themicroneedle layer comprises injection moulding the microneedle layerwithin the cavity of a microneedle layer injection mould.
 46. A methodaccording to claim 45, wherein the injection mould is a microneedlemould as with the first surface of the secondary mould forming a firstsurface of the microneedle mould cavity and the secondary mouldthrough-holes extending into the first surface of the microneedle mouldcavity.
 47. A method according to claim 45, wherein forming themicroneedle layer comprises injection moulding a polymer into the cavityof the microneedle layer injection mould.
 48. A method according toclaim 40, wherein the microneedle layer is formed of metal.
 49. One ormore microneedles manufactured according to the method of claim
 40. 50.One or more microneedles according to claim 49, which are solid.
 51. Amethod of manufacturing a master mould for use in manufacturingmicroneedles, substantially as hereinbefore described, with reference toand as illustrated in the accompanying drawings.
 52. A master mould foruse in manufacturing microneedles, which master mould is constructed andarranged substantially as hereinbefore described, with reference to andas illustrated in the accompanying drawings.
 53. A method ofmanufacturing a secondary mould for use in manufacturing microneedles,substantially as hereinbefore described, with reference to and asillustrated in the accompanying drawings.
 54. A mould for a secondarymould for use in manufacturing microneedles, which mould for a secondarymould is constructed and arranged substantially as hereinbeforedescribed, with reference to and as illustrated in the accompanyingdrawings.
 55. A secondary mould for use in manufacturing microneedles,which secondary mould is constructed and arranged substantially ashereinbefore described, with reference to and as illustrated in theaccompanying drawings.
 56. A method of manufacturing microneedles,substantially as hereinbefore described, with reference to and asillustrated in the accompanying drawings.
 57. A microneedle mould foruse in manufacturing microneedles, which microneedle mould isconstructed and arranged substantially as hereinbefore described, withreference to and as illustrated in the accompanying drawings.
 58. One ormore microneedles constructed and arranged substantially as hereinbeforedescribed, with reference to and as illustrated in the accompanyingdrawings.